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Abstract

Stem cells hold great promise for the clinical treatment of diseases of the central nervous system (CNS), including Parkinson’s disease (PD), Huntington’s disease (HD) and Multiple Sclerosis (MS). In fact, two adult stem cells have been shown to be safe and efficacious in animal models of CNS diseases and are currently in clinical trials – (i) human mesenchymal stem cells (hMSCs), and (ii) human neural precursor cells (hNPCs), a population containing neural stem cells (NSCs). These two adult stem cell lines require different modes to elicit therapeutic benefit in CNS diseases. The beneficial therapeutic effects of hMSCs have been mainly attributed to their secretion of trophic factors (i.e. secretome) that can regulate neural survival, proliferation and differentiation. While, for hNPCs, it is their differentiated progeny (i.e. specific neurons derived from hNPCs) that are able to replace the functional cells lost in these CNS diseases. However, there is a lack of consistency in cell culture methodologies (i.e. bioprocessing) between different researchers in order to produce either the secretome or the differentiated therapeutic cells. Hence, it is of critical importance to address the cell production processes as this can highly affect the clinical benefit elicited from these culture-expanded stem cells.
First, a scalable defined bioprocess was developed for the expansion of human bone marrow-derived MSCs (BM-hMSCs) that was able to enhance the secretion of hMSC neurotrophic factors and promoted the survival and differentiation of immature human γ-aminobutyric acid (GABA) neurons. Preliminary in vivo studies indicate that the BM-hMSC secretome was able to promote the recruitment and differentiation of endogenous NSCs. As the hMSC secretome is not able to directly replace cells lost in CNS diseases, and only provides a therapeutic milieu to support endogenous neural cells, a method was developed for the directed differentiation of hNPCs to a pure population of immature neurons (neuroblasts) for cell replacement strategies. Hence, in a second related project, a pure populations of PSA-NCAM+ neurons were generated (>98%) in normoxic (20% O2) conditions. Hypoxic (2% O2) conditions further drove the differentiation of hNPCs to immature neurons that expressed markers of GABA and dopamine (DA) neurons. The combined transplantation of both the hMSC secretome and hNPC-derived neuroblasts offers great promise in providing a therapeutic treatment for CNS diseases, with an initial target being PD.